To develop clinical approaches that will improve the speed and quality of immune reconstitution after bone marrow transplantation, it is necessary to understand in detail the biology of the primitive cells that engraft and generate short-term and long- term lymphoid production and the mechanisms by which this process is regulated. Many fundamental questions remain about this process in humans. The overall goals of this proposal are to identify and characterize primitive human lymphoid progenitors in clinically relevant sources of Lympho-Hematopoietic Stem Cells (LHSC) and to determine how engraftment and differentiation of extrathymic and thymic human lymphoid progenitors can be manipulated after transplantation. We have recently identified and characterized a human Common Lymphoid Progenitor (CLP) population in umbilical cord blood and have identified a similar population in bone marrow. A number of critical differences exist between human and murine CLP, and between CLP from different hematopoietic sources emphasizing the importance of studying human cells from relevant sources in pre-clinical translational research. Our Specific Aims are (1) To identify and characterize human CLP and other lymphoid progenitors in Mobilized Peripheral Blood (MPB). Emphasis will be given to relative engraftment levels of CLP and LHSC and to CLP from MPB and bone marrow; (2) To determine the thymic migration pattern of human LHSC and lymphoid progenitors during homeostasis and after transplantation; (3) To determine methods to enhance human T lymphopoiesis after MPB transplantation by in vivo and in vitro manipulation of the graft. Complementary expertise from three laboratories using a variety of in vitro and in vivo assays, will be used to critically analyze the biology of human LHSC and CLP, and to develop methods by which engraftment, thymic migration and T lymphopoiesis can be enhanced following transplantation.